3.2 Investigations and treatment
Currently, there is no cure for
osteogenesis imperfecta, but a
series of treatments can be employed to alleviate symptoms and improve
the quality of life. Treatment modalities include pharmacotherapy,
physical therapy, and surgical intervention[10].
Pharmacotherapy involves the use of calcium supplements, vitamin D, and
other nutritional supplements to increase bone density and improve
skeletal health. Physical therapy includes rehabilitation exercises and
orthotic devices to help patients improve posture and mobility. Surgical
intervention is primarily reserved for severe spinal curvature and hip
joint issues[11]. For this patient, we
administered calcium supplements and vitamin D, along with some physical
training, as the patient does not exhibit spinal curvature or joint
deformities and does not currently require surgical intervention.
Discussion:In 1979, Sillence et al[12]. first proposed a
standard classification system for OI based on the severity of clinical
manifestations, ranging from Type I to Type IV. The classifications are
as follows[13]: Type I is associated with mild
clinical features, including blue sclera and no apparent dentinogenesis
imperfecta, and typically does not result in disability; Type II is the
most severe, characterized by blue sclera, a small chest, rib fractures,
pulmonary infections, and often leads to perinatal death due to
respiratory failure; Type III, the most severe survivable type of OI,
typically presents with progressive bodily deformities such as severe
short stature and significant spinal curvature, without blue sclera; and
Type IV is a moderate form of the disease characterized by normal sclera
and incomplete dentinogenesis, with patients exhibiting more severe
clinical features than Type I OI but milder than Type III. In the
present case, the patient’s stature was slightly smaller than that of a
normal newborn, and radiographic examination at 5 months old revealed
slender long bones in the limbs and underdeveloped hip joints. There
were no obvious deformities of the spine or limbs, and the patient did
not have blue sclera. Based on the clinical presentation, the patient
was diagnosed with Type IV OI.
Osteogenic Imperfecta is primarily caused by abnormalities in the
quantity
or structure of Type I collagen. Type I collagen is the primary
component
of the extracellular matrix of bone cells, is the most common type of
collagen in the body, and is found predominantly in tissues such as the
bone, cornea, dermis, and tendons. Therefore, its quantity and quality
are closely related to bone strength[14-15].
COL1A1 is located at 17q21.33, comprising 52 exons. Mutations in this
gene can decrease the quantity or instability of Type I collagen,
resulting in increased bone fragility.
In this case report, through genetic sequencing, we identified a
heterozygous variant in the coding region of the COL1A1 gene
(Chr17:48263290): NM__000088.4:c.4097T>A (p.Ile1366Asn) .
This variant was highly correlated with the clinical phenotype of the
patient, with a REVEL predicted score of 0.878, and was classified as a
likely pathogenic variant according to ACMG
classification[16].
Subsequently, the mutation site was verified using Sanger sequencing.
The COL1A1 c.4097T>A variant occurs at position 4097 in the
coding region of COL1A1, where thymine is replaced by adenine, resulting
in the substitution of isoleucine with asparagine at position 1366 of
the encoded protein. Owing to this amino acid substitution, the
structure of Type I collagen is abnormal,ultimately leading to OI.
COL1A1 gene mutations that cause abnormalities in Type I collagen
structure most commonly involve the substitution of glycine with other
amino acids. Glycine plays a crucial role in the triple helical
structure of collagen, and its substitution disrupts this
structure[17]. In the present case, genetic
testing revealed an amino acid substitution of isoleucine with
asparagine, which was classified as a missense mutation. This mutation
has not been recorded in the GnomAD, ExAC, or Thousand Genomes Project
databases. Furthermore, we found that the patient’s parents did not
harbor this mutation (Table 1), indicating that this variant was likely
a de novo mutation, although the possibility of parental germ cell
mosaicism cannot be ruled out.
In conclusion, OI is a rare genetic disorder, and genetic testing is
crucial for its diagnosis, in addition to analysis of symptoms and
auxiliary examinations. Overall, analysis of the present case revealed a
rare
variant (COL1A1 exon c.4097T>A) that we believe is linked
to Type IV OI in the Chinese population. Overall, the results of the
present study contribute to the current knowledge regarding the spectrum
of pathogenic COL1A1 gene mutations in a Chinese population with OI.References:
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Table 1. Results of genetic testing (SNVs, Indels)
Gene Chromosomal position HGVS nominate Gene subregion Variant type
Zygotic state ACMGgrade
(hg19)
Proband Father Mother
COLIA I chr17: NM-000088.4: Exon50 Missensevariatio Heterozygosis
Wildtype Wild type May cause
48263290 c.4097T>A
diseas
p.Ile1366A sn